Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1.
Identifieur interne : 000373 ( Main/Exploration ); précédent : 000372; suivant : 000374Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1.
Auteurs : Vladimir L. Kolossov [États-Unis] ; Nagendraprabhu Ponnuraj [États-Unis] ; Jessica N. Beaudoin [États-Unis] ; Matthew T. Leslie [États-Unis] ; Paul J. Kenis [États-Unis] ; H Rex Gaskins [États-Unis]Source :
- Biochemical and biophysical research communications [ 1090-2104 ] ; 2017.
Descripteurs français
- KwdFr :
- Antinéoplasiques (pharmacologie), Colorants fluorescents (analyse), Cytosol (effets des médicaments et des substances chimiques), Cytosol (métabolisme), Dicoumarol (pharmacologie), Espèces réactives de l'oxygène (métabolisme), Glutarédoxines (analyse), Glutarédoxines (génétique), Glutathion (analyse), Glutathion (métabolisme), Humains (MeSH), Imagerie moléculaire (MeSH), Indolequinones (pharmacologie), Lignée cellulaire tumorale (MeSH), Mitochondries (effets des médicaments et des substances chimiques), Mitochondries (métabolisme), NADPH dehydrogenase (quinone) (antagonistes et inhibiteurs), NADPH dehydrogenase (quinone) (métabolisme), Naphtoquinones (métabolisme), Oxydoréduction (effets des médicaments et des substances chimiques), Protéines à fluorescence verte (analyse), Protéines à fluorescence verte (génétique), Quinones (pharmacologie), Sondes moléculaires (génétique), Spécificité du substrat (MeSH), Stress oxydatif (effets des médicaments et des substances chimiques), Techniques de biocapteur (MeSH), Thérapie moléculaire ciblée (MeSH).
- MESH :
- analyse : Colorants fluorescents, Glutarédoxines, Glutathion, Protéines à fluorescence verte.
- antagonistes et inhibiteurs : NADPH dehydrogenase (quinone).
- effets des médicaments et des substances chimiques : Cytosol, Mitochondries, Oxydoréduction, Stress oxydatif.
- génétique : Glutarédoxines, Protéines à fluorescence verte, Sondes moléculaires.
- métabolisme : Cytosol, Espèces réactives de l'oxygène, Glutathion, Mitochondries, NADPH dehydrogenase (quinone), Naphtoquinones.
- pharmacologie : Antinéoplasiques, Dicoumarol, Indolequinones, Quinones.
- Humains, Imagerie moléculaire, Lignée cellulaire tumorale, Spécificité du substrat, Techniques de biocapteur, Thérapie moléculaire ciblée.
English descriptors
- KwdEn :
- Antineoplastic Agents (pharmacology), Biosensing Techniques (MeSH), Cell Line, Tumor (MeSH), Cytosol (drug effects), Cytosol (metabolism), Dicumarol (pharmacology), Fluorescent Dyes (analysis), Glutaredoxins (analysis), Glutaredoxins (genetics), Glutathione (analysis), Glutathione (metabolism), Green Fluorescent Proteins (analysis), Green Fluorescent Proteins (genetics), Humans (MeSH), Indolequinones (pharmacology), Mitochondria (drug effects), Mitochondria (metabolism), Molecular Imaging (MeSH), Molecular Probes (genetics), Molecular Targeted Therapy (MeSH), NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors), NAD(P)H Dehydrogenase (Quinone) (metabolism), Naphthoquinones (metabolism), Oxidation-Reduction (drug effects), Oxidative Stress (drug effects), Quinones (pharmacology), Reactive Oxygen Species (metabolism), Substrate Specificity (MeSH).
- MESH :
- chemical , analysis : Fluorescent Dyes, Glutaredoxins, Glutathione, Green Fluorescent Proteins.
- chemical , antagonists & inhibitors : NAD(P)H Dehydrogenase (Quinone).
- chemical , genetics : Glutaredoxins, Green Fluorescent Proteins, Molecular Probes.
- chemical , metabolism : Glutathione, NAD(P)H Dehydrogenase (Quinone), Naphthoquinones, Reactive Oxygen Species.
- chemical , pharmacology : Antineoplastic Agents, Dicumarol, Indolequinones, Quinones.
- drug effects : Cytosol, Mitochondria, Oxidation-Reduction, Oxidative Stress.
- metabolism : Cytosol, Mitochondria.
- Biosensing Techniques, Cell Line, Tumor, Humans, Molecular Imaging, Molecular Targeted Therapy, Substrate Specificity.
Abstract
Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (EGSH) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (β-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors. Immediate oxidation of EGSH in both the cytosol and mitochondrial matrix was observed in response to DNQ and β-lap. The DNQ-induced cytosolic oxidation was fully prevented with NQO1 inhibition, whereas mitochondrial oxidation in A549 was NQO1-independent in contrast to MIA-PaCa-2 cells. However, at pharmacologic concentrations of β-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols. Together, these data provide new evidence that DNQ's direct and discerning NQO1 substrate specificity underlies its pharmacologic potency, while β-lap elicits off-target responses at its effective doses.
DOI: 10.1016/j.bbrc.2016.12.082
PubMed: 27986568
PubMed Central: PMC5253246
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic Agents (pharmacology)</term>
<term>Biosensing Techniques (MeSH)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cytosol (drug effects)</term>
<term>Cytosol (metabolism)</term>
<term>Dicumarol (pharmacology)</term>
<term>Fluorescent Dyes (analysis)</term>
<term>Glutaredoxins (analysis)</term>
<term>Glutaredoxins (genetics)</term>
<term>Glutathione (analysis)</term>
<term>Glutathione (metabolism)</term>
<term>Green Fluorescent Proteins (analysis)</term>
<term>Green Fluorescent Proteins (genetics)</term>
<term>Humans (MeSH)</term>
<term>Indolequinones (pharmacology)</term>
<term>Mitochondria (drug effects)</term>
<term>Mitochondria (metabolism)</term>
<term>Molecular Imaging (MeSH)</term>
<term>Molecular Probes (genetics)</term>
<term>Molecular Targeted Therapy (MeSH)</term>
<term>NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors)</term>
<term>NAD(P)H Dehydrogenase (Quinone) (metabolism)</term>
<term>Naphthoquinones (metabolism)</term>
<term>Oxidation-Reduction (drug effects)</term>
<term>Oxidative Stress (drug effects)</term>
<term>Quinones (pharmacology)</term>
<term>Reactive Oxygen Species (metabolism)</term>
<term>Substrate Specificity (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antinéoplasiques (pharmacologie)</term>
<term>Colorants fluorescents (analyse)</term>
<term>Cytosol (effets des médicaments et des substances chimiques)</term>
<term>Cytosol (métabolisme)</term>
<term>Dicoumarol (pharmacologie)</term>
<term>Espèces réactives de l'oxygène (métabolisme)</term>
<term>Glutarédoxines (analyse)</term>
<term>Glutarédoxines (génétique)</term>
<term>Glutathion (analyse)</term>
<term>Glutathion (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Imagerie moléculaire (MeSH)</term>
<term>Indolequinones (pharmacologie)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Mitochondries (effets des médicaments et des substances chimiques)</term>
<term>Mitochondries (métabolisme)</term>
<term>NADPH dehydrogenase (quinone) (antagonistes et inhibiteurs)</term>
<term>NADPH dehydrogenase (quinone) (métabolisme)</term>
<term>Naphtoquinones (métabolisme)</term>
<term>Oxydoréduction (effets des médicaments et des substances chimiques)</term>
<term>Protéines à fluorescence verte (analyse)</term>
<term>Protéines à fluorescence verte (génétique)</term>
<term>Quinones (pharmacologie)</term>
<term>Sondes moléculaires (génétique)</term>
<term>Spécificité du substrat (MeSH)</term>
<term>Stress oxydatif (effets des médicaments et des substances chimiques)</term>
<term>Techniques de biocapteur (MeSH)</term>
<term>Thérapie moléculaire ciblée (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Fluorescent Dyes</term>
<term>Glutaredoxins</term>
<term>Glutathione</term>
<term>Green Fluorescent Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>NAD(P)H Dehydrogenase (Quinone)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Glutaredoxins</term>
<term>Green Fluorescent Proteins</term>
<term>Molecular Probes</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glutathione</term>
<term>NAD(P)H Dehydrogenase (Quinone)</term>
<term>Naphthoquinones</term>
<term>Reactive Oxygen Species</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Dicumarol</term>
<term>Indolequinones</term>
<term>Quinones</term>
</keywords>
<keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>Colorants fluorescents</term>
<term>Glutarédoxines</term>
<term>Glutathion</term>
<term>Protéines à fluorescence verte</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>NADPH dehydrogenase (quinone)</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cytosol</term>
<term>Mitochondria</term>
<term>Oxidation-Reduction</term>
<term>Oxidative Stress</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Cytosol</term>
<term>Mitochondries</term>
<term>Oxydoréduction</term>
<term>Stress oxydatif</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Glutarédoxines</term>
<term>Protéines à fluorescence verte</term>
<term>Sondes moléculaires</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cytosol</term>
<term>Mitochondria</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cytosol</term>
<term>Espèces réactives de l'oxygène</term>
<term>Glutathion</term>
<term>Mitochondries</term>
<term>NADPH dehydrogenase (quinone)</term>
<term>Naphtoquinones</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Dicoumarol</term>
<term>Indolequinones</term>
<term>Quinones</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Biosensing Techniques</term>
<term>Cell Line, Tumor</term>
<term>Humans</term>
<term>Molecular Imaging</term>
<term>Molecular Targeted Therapy</term>
<term>Substrate Specificity</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Humains</term>
<term>Imagerie moléculaire</term>
<term>Lignée cellulaire tumorale</term>
<term>Spécificité du substrat</term>
<term>Techniques de biocapteur</term>
<term>Thérapie moléculaire ciblée</term>
</keywords>
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<front><div type="abstract" xml:lang="en">Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (E<sub>GSH</sub>
) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (β-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors. Immediate oxidation of E<sub>GSH</sub>
in both the cytosol and mitochondrial matrix was observed in response to DNQ and β-lap. The DNQ-induced cytosolic oxidation was fully prevented with NQO1 inhibition, whereas mitochondrial oxidation in A549 was NQO1-independent in contrast to MIA-PaCa-2 cells. However, at pharmacologic concentrations of β-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols. Together, these data provide new evidence that DNQ's direct and discerning NQO1 substrate specificity underlies its pharmacologic potency, while β-lap elicits off-target responses at its effective doses.</div>
</front>
</TEI>
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<DateCompleted><Year>2017</Year>
<Month>05</Month>
<Day>29</Day>
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<DateRevised><Year>2019</Year>
<Month>01</Month>
<Day>09</Day>
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<Issue>1</Issue>
<PubDate><Year>2017</Year>
<Month>01</Month>
<Day>29</Day>
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<Title>Biochemical and biophysical research communications</Title>
<ISOAbbreviation>Biochem Biophys Res Commun</ISOAbbreviation>
</Journal>
<ArticleTitle>Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1.</ArticleTitle>
<Pagination><MedlinePgn>680-686</MedlinePgn>
</Pagination>
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<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.bbrc.2016.12.082</ELocationID>
<Abstract><AbstractText>Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (E<sub>GSH</sub>
) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (β-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors. Immediate oxidation of E<sub>GSH</sub>
in both the cytosol and mitochondrial matrix was observed in response to DNQ and β-lap. The DNQ-induced cytosolic oxidation was fully prevented with NQO1 inhibition, whereas mitochondrial oxidation in A549 was NQO1-independent in contrast to MIA-PaCa-2 cells. However, at pharmacologic concentrations of β-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols. Together, these data provide new evidence that DNQ's direct and discerning NQO1 substrate specificity underlies its pharmacologic potency, while β-lap elicits off-target responses at its effective doses.</AbstractText>
<CopyrightInformation>Copyright © 2016 Elsevier Inc. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kolossov</LastName>
<ForeName>Vladimir L</ForeName>
<Initials>VL</Initials>
<AffiliationInfo><Affiliation>Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: viadimer@illinois.edu.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ponnuraj</LastName>
<ForeName>Nagendraprabhu</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Beaudoin</LastName>
<ForeName>Jessica N</ForeName>
<Initials>JN</Initials>
<AffiliationInfo><Affiliation>Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.</Affiliation>
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<AffiliationInfo><Affiliation>Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.</Affiliation>
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<AffiliationInfo><Affiliation>Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.</Affiliation>
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<ForeName>H Rex</ForeName>
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<AffiliationInfo><Affiliation>Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.</Affiliation>
</AffiliationInfo>
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<Language>eng</Language>
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<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
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<Month>12</Month>
<Day>14</Day>
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<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
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<MeshHeading><DescriptorName UI="D015374" MajorTopicYN="N">Biosensing Techniques</DescriptorName>
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<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading><DescriptorName UI="D054477" MajorTopicYN="N">Glutaredoxins</DescriptorName>
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<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
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<QualifierName UI="Q000032" MajorTopicYN="N">analysis</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
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<MeshHeading><DescriptorName UI="D045563" MajorTopicYN="N">Indolequinones</DescriptorName>
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<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
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<MeshHeading><DescriptorName UI="D016660" MajorTopicYN="N">NAD(P)H Dehydrogenase (Quinone)</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading><DescriptorName UI="D010084" MajorTopicYN="N">Oxidation-Reduction</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
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<MeshHeading><DescriptorName UI="D018384" MajorTopicYN="N">Oxidative Stress</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
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<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
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<MeshHeading><DescriptorName UI="D017382" MajorTopicYN="N">Reactive Oxygen Species</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading><DescriptorName UI="D013379" MajorTopicYN="N">Substrate Specificity</DescriptorName>
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<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">DNQ and β-lapachone</Keyword>
<Keyword MajorTopicYN="Y">Lung and pancreatic cancer</Keyword>
<Keyword MajorTopicYN="Y">NQO1</Keyword>
<Keyword MajorTopicYN="Y">Redox homeostasis</Keyword>
<Keyword MajorTopicYN="Y">roGFP2 redox probe</Keyword>
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<CoiStatement>The authors declare no conflict of interest.</CoiStatement>
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<affiliations><list><country><li>États-Unis</li>
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<tree><country name="États-Unis"><region name="Illinois"><name sortKey="Kolossov, Vladimir L" sort="Kolossov, Vladimir L" uniqKey="Kolossov V" first="Vladimir L" last="Kolossov">Vladimir L. Kolossov</name>
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<name sortKey="Beaudoin, Jessica N" sort="Beaudoin, Jessica N" uniqKey="Beaudoin J" first="Jessica N" last="Beaudoin">Jessica N. Beaudoin</name>
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<name sortKey="Ponnuraj, Nagendraprabhu" sort="Ponnuraj, Nagendraprabhu" uniqKey="Ponnuraj N" first="Nagendraprabhu" last="Ponnuraj">Nagendraprabhu Ponnuraj</name>
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